Influenza remains a continual threat to health of many Americans, resulting in 9.2-35.6 million illnesses, 140,000-710,000 hospitalizations, and 12,000-56,000 deaths annually since 2010 (CDC), as well as the ever-present likelihood of a devastating pandemic that could kill millions. Recent work has also suggested that a universal flu vaccine may be possible, although there is considerable uncertainty about how to achieve this. This renewal application seeks to leverage some of the important methodologies and data that we have developed in this past granting period to understand at a much deeper level what constitutes broad and effective B and T cell responses against influenza so as to better inform next generation vaccine efforts. Specifically, we have developed a unique tonsil organoid system that we can expose to a flu vaccine and produce high affinity antibodies several days to a week later. This gives us an ability to manipulate and test vaccine constructs and adjuvants in a fully human system in order to find the best way to trigger broadly neutralizing antibodies. In addition, we have developed powerful new T and B cell repertoire analysis methods that will allow us to productively analyze large flu- specific TCR and Ig data sets to identify which specificities or other correlates contribute the most to protection or amelioration of diseases in challenge studies. We also plan to further analyze influenza vaccine responses in pregnant women, the elderly and twins, to test various hypotheses that we have developed in our previous work in the CCHI. Lastly we will take advantage of recent advances by the Nolan lab in imaging tissue sections with large numbers of different antibodies to analyze the cellular organization the tonsil organoids with time during a flu vaccine response and after different interventions.

Public Health Relevance

Influenza morbidity and mortality cause a significant global health burden due to the lack of a universal vaccine. The goal of the Stanford CCHI is to provide missing immunologic data through novel organoid systems derived from tonsils and lymph nodes, lymphocyte repertoire analysis, and 2D/3D cellular neighborhoods and spatial interactions. We will utilize these approaches to determine important characteristics of broadly-neutralizing antibodies, delivery systems and adjuvants, and prior immunity and ?imprinting? of influenza exposures which will contribute to the development of a universal influenza vaccine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
2U19AI057229-16
Application #
9674968
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Jiang, Chao
Project Start
2003-09-30
Project End
2024-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
16
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Davis, Mark M; Tato, Cristina M (2018) Will Systems Biology Deliver Its Promise and Contribute to the Development of New or Improved Vaccines? Seeing the Forest Rather than a Few Trees. Cold Spring Harb Perspect Biol 10:
Gee, Marvin H; Han, Arnold; Lofgren, Shane M et al. (2018) Antigen Identification for Orphan T Cell Receptors Expressed on Tumor-Infiltrating Lymphocytes. Cell 172:549-563.e16
Keeffe, Jennifer R; Van Rompay, Koen K A; Olsen, Priscilla C et al. (2018) A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates. Cell Rep 25:1385-1394.e7
Wagar, Lisa E; DiFazio, Robert M; Davis, Mark M (2018) Advanced model systems and tools for basic and translational human immunology. Genome Med 10:73
Good, Zinaida; Sarno, Jolanda; Jager, Astraea et al. (2018) Single-cell developmental classification of B cell precursor acute lymphoblastic leukemia at diagnosis reveals predictors of relapse. Nat Med 24:474-483
Satpathy, Ansuman T; Saligrama, Naresha; Buenrostro, Jason D et al. (2018) Transcript-indexed ATAC-seq for precision immune profiling. Nat Med 24:580-590
Vallania, Francesco; Tam, Andrew; Lofgren, Shane et al. (2018) Leveraging heterogeneity across multiple datasets increases cell-mixture deconvolution accuracy and reduces biological and technical biases. Nat Commun 9:4735
Bongen, Erika; Vallania, Francesco; Utz, Paul J et al. (2018) KLRD1-expressing natural killer cells predict influenza susceptibility. Genome Med 10:45
Sweeney, Timothy E; Azad, Tej D; Donato, Michele et al. (2018) Unsupervised Analysis of Transcriptomics in Bacterial Sepsis Across Multiple Datasets Reveals Three Robust Clusters. Crit Care Med 46:915-925
Lin, Dongxia; Maecker, Holden T (2018) Mass Cytometry Assays for Antigen-Specific T Cells Using CyTOF. Methods Mol Biol 1678:37-47

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